Over the last years, various approaches have been proposed to improve the delivery of drugs at the target site. First, the drug must be administered by a suitable and easy route, such as orally or rectally, and second the active ingredient must be delivered at the target cells under an active form. There is no device currently available allowing such a vectorized transport of active molecules.
Many publications and patents describe methods for encapsulating active ingredients into nano or micro-particles, but the issue, to date unsolved, is to provide both an easy route of administration different from the injectable route, such as oral and buccal routes, and an efficient delivery of the active product at the target sites.
The inventors have previously uncovered that stirring two types of lipids with some metallic salts allowed to increase salt bioavailability and consequently to obtain same therapeutic activity with 1000 to 5000 times lower doses; the potential toxicity of said salts could then be reduced [see U.S. Pat. No. 6,129,924, WO 02/36134 and WO 2004/075990, for instance].
The inventors in particular identified novel products indicated under the term “organometallic complexes”, and obtained by reaction between a derivative of vanadium in oxidation state 4 or 5 and two organic compounds isolated from plant extracts and respectively constituted of sitosterol and acylglycerols.
The inventors also discovered that similar complexes could be prepared from other derivatives of metals wherein the metal is for instance known for its antidiabetic activity.
They also discovered that similar complexes could be obtained from the organic derivatives mentioned previously and various cations of metals useful as biocatalysts in living metabolism, these complexes being particularly effective agents as vectors of said cations. Such vectorization of metallic cations affords an important decrease of the toxicity of administered cations compared to their administration in the absence of micelles as previously described. Actually, the use of such complexes, as described in WO2006/048773, allows efficient vectorization of the cations to target sites and thus allows administration of far lower amounts of metal. For instance, the use of these complexes affords obtaining the same therapeutic activity with 1000 to 10000 times lower doses.
Such complexes have been shown effective to vectorize metallic cations in small quantities, for instance lower than 80 μg of lithium, per ml of formulation. If such amounts are sufficient to compare the therapeutic activity of cations in animals, transposition to the human scale requires higher amounts of cations to be administered. The stability of microemulsions containing higher quantities of metal is not always satisfactory to allow their development as delivery systems for drugs and/or dietetic compounds for example.
Incorporation of a phospholipid or a sphingolipid, in particular in specific amounts, in the formulation of microemulsions comprising higher doses of metal ions surprisingly triggered an important increase in their stability.
The present invention describes new microemulsions formulations able to vectorize high quantities of metal ions, process of preparation and use thereof as delivery systems for drugs and/or dietetic compounds. “High” amounts refer here to amounts sufficient to obtain a therapeutic activity at the human scale, but that remain far lower than the amounts of cations delivered in absence of complexes. The reverse micelle system of the present invention may for instance allow vectorization of up to 1500 μg of metal per ml of formulation.
This formulation advantageously renders possible the control and optimisation of the composition comprising micelles for their uses in the pharmaceutical and dietetic fields.